Absorption, disposition, and pharmacokinetics of saponins from Chinese medicinal herbs: What do we know and what do we need to know more?

Current Drug Metabolism

Volumn 13, Issue 5, 2012, Pages 577-598

  Yu, Ke ^a   Chen, Feng ^a,b   Li, Chuan ^a  

^a SHANGHAI INSTITUTE OF MATERIA MEDICA   (China)

^b HAINAN MEDICAL UNIVERSITY   (China)

Author keywords

Absorption; Disposition; Ginsenoside; Panax; Saponin

Indexed keywords

ASTRAGALOSIDE IV; COMPOUND K; CYTOCHROME P450 3A4; DIOSCIN; GINSENOSIDE F1; GINSENOSIDE RA3; GINSENOSIDE RB 1; GINSENOSIDE RC; GINSENOSIDE RD; GINSENOSIDE RE; GINSENOSIDE RF; GINSENOSIDE RF2; GINSENOSIDE RG 1; GINSENOSIDE RG 3; GINSENOSIDE RH 2; GINSENOSIDE RH1; GLYCYRRHETINIC ACID; GLYCYRRHIZIC ACID; METHYLPROTODIOSCIN; NOTOGINSENOSIDE R1; PROTODIOSCIN; PROTOPANAXATRIOL; SAIKOSAPONIN A; SAPONIN DERIVATIVE; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; ARTICLE; BILIARY EXCRETION; CHINESE MEDICINE; DEGLYCOSYLATION; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG DEGRADATION; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG METABOLISM; DRUG STRUCTURE; DRUG UPTAKE; IN VITRO STUDY; IN VIVO STUDY; INTESTINE ABSORPTION; LIVER METABOLISM; MAXIMUM PLASMA CONCENTRATION; MEMBRANE PERMEABILITY; MICROFLORA; PHYSICAL CHEMISTRY; URINARY EXCRETION;

EID: 84861891478     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/1389200211209050577     Document Type: Article

References (239)

1. Vincken, J.P.; Heng, L.; de Groot, A.; Gruppen, H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry, 2007, 68(3), 275-297.
2. Price, K.R.; Johnson, I.T.; Fenwick, G.R. The chemistry and biological significance of saponins in foods and feedingstuffs. Crit. Rev. Food Sci. Nutr., 1987, 26(1), 27-135.
3. Shi, J.; Arunasalam, K.; Yeung, D.; Kakuda, Y.; Mittal, G.; Jiang, Y. Saponins from edible legumes: chemistry, processing, and health benefits. J. Med. Food, 2004, 7(1), 67-78.
4. Güçlü-Ustündaǧ, Ö.; Mazza, G. Saponins: properties, applications and processing. Crit. Rev. Food Sci. Nutr., 2007, 47(3), 231-258.
5. Rao, A-V.; Gurfinkel, D.M. The bioactivity of saponins: triterpenoid and steroidal glycosides. Drug Metabol. Drug Interact., 2000, 17(1-4), 211-235.
6. Francis, G.; Kerem, Z.; Makkar, H.P.; Becker, K. The biological action of saponins in animal systems: a review. Br. J. Nutr., 2002, 88(6), 587-605.
7. Sparg, S.G.; Light, M.E.; van Staden, J. Biological activities and distribution of plant saponins. J. Ethnopharmacol., 2004, 94(2-3), 219-243.
8. George, A.J. Legal status and toxicity of Saponins. Food Cosmet. Toxicol., 1965, 3(1), 85-91.
9. Gauthier, C.; Legault, J.; Girard-Lalancette, K.; Mshvildadze, V.; Pichette, A. Haemolytic activity, cytotoxicity and membrane cell permeabilization of semi-synthetic and natural lupine- and oleanane-type saponins. Bioorg. Med. Chem., 2009, 17(5), 2002-2008.
10. Takechi, M.; Tanaka, Y. Haemolytic time course differences between steroid and triterpenoid saponins. Planta Med., 1995, 61(1), 76-77.
11. Santos, W.R.; Bernardo, R.R.; Peçanha, L.M.; Palatnik, M.; Parente, J.P.; Palatnik de Sousa, C.B. Haemolytic activities of plant saponins and adjuvants. Effect of Periandra mediterranea saponin on the humoral response to the FML antigen of Leishmania donovani. Vaccine, 1997, 15(9), 1024-1029.
12. Voutquenne, L.; Lavaud, C.; Massiot, G.; Men-Olivier, L.L. Structure- activity relationship of haemolytic saponins. Pharm. Biol., 2002, 40(4), 352-262.
13. Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China, vol I; People's Medical Publishing House: Beijing, 2010, pp. 8 (Renshen), 11 (Sanqi), 27 (Shanyao), 80-81 (Gancao), 122 (Xiyangshen), 250 (Chuanshanlong), 263 (Chaihu), 271 (Fenbixie), 282 (Huangshanyao), 283 (Huangqi), and 311(Mianbixie).
14. Christensen, L.P. Ginsenosides: chemistry, biosynthesis, analysis, and potential health effects. Adv. Food Nutr. Res., 2009, 55(1), 1-99.
15. Qi, L-W.; Wang, C-Z.; Yuan, C-S. Isolation and analysis of ginseng: advances and challenges. Nat. Prod. Rep., 2011, 28(3), 467-495.
16. Sollorz, G. Quality evaluation of ginseng root, quantitative HPLCdetermination of ginsenosides. Deutsch. Apoth. Ztg., 1985, 125(41), 2052-2055.
17. Wang, X.; Sakuma, T.; Asafu-Adjaye, E.; Shiu, G.K. Determination of ginsenosides in plant extracts from Panax ginseng and Panax quinquefolius L. by LC/MS/MS. Anal. Chem., 1999, 71(8), 1579-1584.
18. Ma, Y-C.; Luo, M.; Mally, L.; Doucer, M. Distribution and proportion of major ginsenosides and quality control of ginseng products. Chin. J. Med. Chem., 1996, 6(1), 11-21.
19. Li, W.; Gu, C.; Zhang, H.; Awang, D.V.; Fitzloff, J.F.; Fong, H.H.; van Breemen, R.B. Use of high-performance liquid chromatography- tandem mass spectrometry to distinguish Panax ginseng C. A. Meyer (Asian ginseng) and Panax quinquefolius L. (North American ginseng). Anal. Chem., 2000, 72(21), 5417-5422.
20. Chan, T.W.; But, P.P.; Cheng, S.W.; Kwok, I.M.; Lau, F.W.; Xu, H.X. Differentiation and authentication of Panax ginseng, Panax quinquefolius, and ginseng products by using HPLC/MS. Anal. Chem., 2000, 72(6), 1281-1287.
21. Guan, J.; Lai, C-M.; Li, S-P. A rapid method for the simultaneous determination of 11 saponins in Panax notoginseng using ultra performance liquid chromatography. J. Pharm. Biomed. Anal., 2007, 44(4), 996-1000.
22. Wan, J-B.; Lai, C-M.; Li, S-P.; Lee, M-Y.; Kong, L-Y.; Wang, YT. Simultaneous determination of nine saponins from Panax notoginseng using HPLC and pressurized liquid extraction. J. Pharm. Biomed. Anal., 2006, 41(1), 274-279.
23. Jia, L.; Zhao, Y. Current evaluation of the millennium phytomedicine- ginseng (I): etymology, pharmacognosy, phytochemistry, market and regulations. Curr. Med. Chem., 2009, 16(19), 2475-2484.
24. Angelova, N.; Kong, H-W.; van der Heijden, R.; Yang, S-Y.; Choi, Y-H.; Kim, H-K.; Wang, M.; Hankemeier, T.; van der Greef, J.; Xu, G-W.; Verpoorte, R. Recent methodology in the phytochemical analysis of ginseng. Phytochem. Anal., 2008, 19(1), 2-16.
25. Sun, H-X.; Qin, F.; Ye, Y-P. Relationship between haemolytic and adjuvant activity and structure of protopanaxadiol-type saponins from the roots of Panax notoginseng. Vaccine, 2005, 23(48-49), 5533-5542.
26. Sun, H-X.; Yang, Z-G.; Ye, Y-P. Structure and biological activity of protopanaxatriol-type saponins from the roots of Panax notoginseng. Int. Immunopharmacol., 2006, 6(1), 14-25.
27. Nah, S-Y.; Kim, D-H.; Rhim, H. Ginsenosides: are any of them candidates for drugs acting on the central nervous system? CNS Drug Rev., 2007, 13(4), 381-404.
28. Choi, K-T. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol. Sin., 2008, 29(9), 1109-1118.
29. Lu, J-M.; Yao, Q-Z.; Chen, C-Y. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr. Vasc. Pharmacol., 2009, 7(3), 293-302.
30. Jia, L.; Zhao, Y-Q.; Liang, X-J. Current evaluation of the millennium phytomedicine- ginseng (II): Collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine. Curr. Med. Chem., 2009, 16(22), 2924-2942.
31. Sengupta, S.; Toh, S-A.; Sellers, L.A.; Skepper, J.N.; Koolwijk, P.; Leung, H-W.; Yeung, H-W.; Wong, R.N.; Sasisekharan, R.; Fan, T-P. Modulating angiogenesis: the yin and the yang in ginseng. Circulation, 2004, 110(10), 1219-1225.
32. Liu, H-F.; Yang, J-L.; Du, F-F.; Gao, X-M.; Ma, X-T.; Huang, YH.; Xu, F.; Niu, W.; Wang, F-Q.; Mao, Y.; Sun, Y.; Lu, T.; Liu, CX.; Zhang, B-L.; Li, C. Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab. Dispos., 2009, 37(12), 2290-2298.
33. Li, X-Y.; Wang, G-J.; Sun, J-G.; Hao, H-P.; Xiong, Y-P.; Yan, B.; Zheng, Y-T.; Sheng, L-S. Pharmacokinetic and absolute bioavailability study of total panax notoginsenoside, a typical multiple constituent traditional Chinese medicine (TCM) in rats. Biol. Pharm. Bull., 2007, 30(5), 847-851.
34. Odani, T.; Tanizawa, H.; Takino, Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. II. The absorption, distribution and excretion of ginsenoside Rg1 in the rat. Chem. Pharm. Bull., 1983, 31(1), 292-298.
35. Odani, T.; Tanizawa, H.; Takino, Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb1 in the rat. Chem. Pharm. Bull., 1983, 31(3), 1059-1066.
36. Xu, Q-F.; Fang, X-L.; Chen, D-F. Pharmacokinetics and bioavailability of ginsenoside Rb1 and Rg1 from Panax notoginseng in rats. J. Ethnopharmacol., 2003, 84(2-3), 187-192.
37. Wang, W.; Wang, G-J.; Xie, H-T.; Sun, J-G.; Zhao, S.; Jiang, X-L.; Li, H.; Lv, H.; Xu, M-J.; Wang, R. Determination of ginsenoside Rd in dog plasma by liquid chromatography-mass spectrometry after solid-phase extraction and its application in dog pharmacokinetics studies. J. Chromatogr. B, 2007, 852(1-2), 8-14.
38. Lai, L.; Hao, H-P; Liu, Y-T; Zheng, C-N.; Wang, Q.; Wang, G-J.; Chen, X. Characterization of pharmacokinetic profiles and metabolic pathways of 20(S)-ginsenoside Rh1 in vivo and in vitro. Planta Med., 2009, 75(8), 797-802.
39. Joo, K-M.; Lee, J-H.; Jeon, H-Y.; Park, C-W.; Hong, D-K.; Jeong, H-J.; Lee, S-J.; Lee, S-Y.; Lim, K-M. Pharmacokinetic study of ginsenoside Re with pure ginsenoside Re and ginseng berry extracts in mouse using ultra performance liquid chromatography/mass spectrometric method. J. Pharm. Biomed. Anal., 2010, 51(1), 278-283.
40. Gu, Y.; Wang, G-J.; Sun, J-G.; Jia, Y-W.; Wang, W.; Xu, M-J.; Lv, T.; Zheng, Y-T.; Sai, Y. Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs. Food Chem. Toxicol., 2009, 47(9), 2257-2268.
41. Paek, I-B.; Moon, Y.; Kim, J.; Ji, H-Y.; Kim, S-A.; Sohn, D-H.; Kim, J-B.; Lee, H-S. Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm. Drug Dispos., 2006, 27(1), 39-45.
42. Ren, H-C.; Sun, J-G.; Wang, G-J.; A, J-Y.; Xie, H-T.; Zha, W-B.; Yan, B.; Sun, F-Z.; Hao, H-P.; Gu, S-H.; Sheng, L-S.; Shao, F.; Shi, J.; Zhou, F. Sensitive determination of 20(S)-protopanaxadiol in rat plasma using HPLC-APCI-MS: application of pharmacokinetic study in rats. J. Pharm. Biomed. Anal., 2008, 48(5), 1476-1480.
43. Ji H-Y.; Lee H-W.; Kim H-K.; Kim H-H.; Chang S-G.; Sohn D-H.; Kim J-B.; Lee H-S. Simultaneous determination of ginsenoside Rb1 and Rg1 in human plasma by liquid chromatography-mass spectrometry. J. Pharm. Biomed. Anal., 2004, 35(1), 207-212.
44. Yang, L.; Xu, S-J.; Wu, Z-F.; Liu, Y-M.; Zeng, X. Determination of ginsenoside-Rg1 in human plasma and its application to pharmacokinetic studies following intravenous administration of 'Shenmai' injection. Phytother. Res., 2009, 23(1), 65-71.
45. Han, M.; Fu, S.; Fang, X-L. Comparison between the characteristics of absorption and pharmacokinetic behavior of ginsenoside Rg1 and ginsenoside Rb1, of Panax notoginseng saponins. Yao Xue Xue Bao, 2007, 42(8), 849-853.
46. Gu, Y.; Wang, G-J.; Sun, J-G.; Jia, Y-W.; Xu, M-J.; Wang, W. In vitro assessment of plasma protein binding of 20(R)-ginsenoside Rh2 by equilibrium dialysis and LC-MS analysis: a case of species differences. Biol. Pharm. Bull., 2006, 29(5), 951-956.
47. Kobashi, K.; Akao, T. Relation of intestinal bacteria to pharmacological effects of glycosides. Biosci. Microflora, 1997, 16(1), 1-7.
48. Yang, L.; Liu, Y.; Liu, C-X. Metabolism and pharmacokinetics of ginsenosides. Asian J. Pharmacod. Pharmacokinet., 2005, 6(2), 103-120.
49. Hasegawa, H.; Sung, J-H.; Matsumiya, S.; Uchiyama, M. Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med., 1996, 62(5), 453-457.
50. Hasegawa, H.; Sung, J-H.; Benno, Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins. Planta Med., 1997, 63(5), 436-440.
51. Bae, E-A.; Park, S-Y.; Kim, D-H. Constitutive β-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol. Pharm. Bull., 2000, 23(12), 1481-1485.
52. Bae, E-A.; Choo, M-K.; Park, E-K.; Park, S-Y.; Shin, H-Y.; Kim, D-H. Metabolism of ginsenoside Rc by human intestinal bacteria and its related antiallergic activity. Biol. Pharm. Bull., 2002, 25(6), 743-747.
53. Bae, E-A.; Shin, J-E.; Kim, D-H. Metabolism of ginsenoside Re by human intestinal microflora and its estrogenic effect. Biol. Pharm. Bull., 2005, 28(10), 1903-1908.
54. Wang, Y.; Liu, T-H.; Wang, W.; Wang, B-X. Research on the transformation of ginsenoside Rg1 by intestinal flora. Zhongguo Zhong Yao Za Zhi, 2001, 26(3), 188-190.
55. Tawab, M.A.; Bahr, U.; Karas, M.; Wurglics, M.; Schubert- Zsilavecz, M. Degradation of ginsenosides in humans after oral administration. Drug Metab. Dispos., 2003, 31(8), 1065-1071.
56. Odani, T.; Tanizawa, H.; Takino, Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. IV. Decomposition of ginsenoside-Rg1 and -Rb1 in the digestive tract of rats. Chem. Pharm. Bull., 1983, 31(10), 3691-3697.
57. Takino, Y. Studies on the pharmacodynamics of ginsenoside-Rg1, - Rb1 and -Rb2 in rats. Yakugaku Zasshi, 1994, 114(8), 550-564.
58. Gu, Y.; Wang, G-J.; Wu, X-L.; Zheng, Y-T.; Zhang, J-W.; Ai, H.; Sun, J-G.; Jia, Y-W. Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters. Xenobiotica, 2010, 40(9), 602-612.
59. Qian, T-X.; Jiang, Z-H.; Cai, Z-W. High-performance liquid chromatography coupled with tandem mass spectrometry applied for metabolic study of ginsenoside Rb1 on rat. Anal. Biochem., 2006, 352(1), 87-96.
60. Yang, L.; Deng, Y-H.; Xu, S-J.; Zeng, X. In vivo pharmacokinetic and metabolism studies of ginsenoside Rd. J. Chromatogr. B, 2007, 854(1-2), 77-84.
61. Yang, L.; Xu, S-J.; Liu, C-J.; Su, Z-J. In vivo metabolism study of ginsenoside Re in rat using high-performance liquid chromatography coupled with tandem mass spectrometry. Anal. Bioanal. Chem., 2009, 395(5), 1441-1451.
62. Qian, T-X.; Cai, Z-W.; Wong, R.N.; Mak, N.K.; Jiang, Z-H. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J. Chromatogr. B, 2005, 816(1-2), 223-232.
63. Kasai, R.; Hara, K.; Dokan, R.; Suzuki, N.; Mizutare, T.; Yoshihara, S.; Yamasaki, K. Major metabolites of ginseng sapogenins formed by rat liver microsomes. Chem. Pharm. Bull., 2000, 48(8), 1226-1227.
64. Li, L.; Chen, X-Y.; Li, D.; Zhong, D-F. Identification of 20(s)- protopanaxadiol metabolites in human liver microsomes and human hepatocytes. Drug Metab. Dispos., 2011, 39(3), 472-483.
65. Hao, H-P.; Lai, L.; Zheng, C-N.; Wang, Q.; Yu, G.; Zhou, X-Y.; Wu, L.; Gong, P.; Wang, G-J. Microsomal cytochrome P450 mediated metabolism of protopanaxatriol ginsenosides: metabolites profile, reaction phenotyping, and structure metabolism relationship. Drug Metab. Dispos., 2010, 38(10), 1731-1739.
66. Janetzky, K.; Morreale, A.P. Probable interaction between warfarin and ginseng. Am. J. Health. Syst. Pharm., 1997, 54(6), 692-693.
67. Yuan, C-S.; Wei, G.; Dey, L.; Karrison, T.; Nahlik, L.; Maleckar, S.; Kasza, K.; Ang-Lee, M.; Moss, J. Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled trial. Ann. Intern. Med., 2004, 141(1), 23-27.
68. Jiang, X.; Williams, K.M.; Liauw, W.S.; Ammit, A.J.; Roufogalis, B.D.; Duke, C.C.; Day, R.O.; McLachlan, A.J. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br. J. Clin. Pharmacol., 2004, 57(5), 592-599.
69. Kaminsky, L.S.; Zhang, Z-Y. Human P450 metabolism of warfarin. Pharmacol. Ther., 1997, 73(1), 67-74.
70. Henderson, G.L.; Harkey, M.R.; Gershwin, M.E.; Hackman, R.M.; Stern, J.S.; Stresser, D.M. Effects of ginseng components on c- DNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci., 1999, 65(15), PL209-214.
71. Li, Y.; Wang, Q.; Yao, X-M.; Li, Y. Induction of CYP3A4 and MDR1 gene expression by baicalin, baicalein, chlorogenic acid, and ginsenoside Rf through constitutive androstane receptor- and pregnane X receptor-mediated pathways. Eur. J. Pharmacol., 2010, 640(1-3), 46-54.
72. Zhu, M.; Chan, K-W.; Ng, L-S.; Chang, Q.; Chang, S.; Li, R.C. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J. Pharm. Pharmacol., 1999, 51(2), 175-180.
73. Thummel, K.E.; Wilkinson, G.R. In vitro and in vivo drug interactions involving human CYP3A. Annu. Rev. Pharmacol. Toxicol., 1998, 38, 389-430.
74. Blanchard, N.; Richert, L.; Coassolo, P.; Lave, T. Qualitative and quantitative assessment of drug-drug interaction potential in man, based on Ki, IC50 and inhibitor concentration. Curr. Drug Metab., 2004, 5(2), 147-156.
75. Rodrigues, A.D.; Lin, J-H. Screening of drug candidates for their drug-drug interaction potential. Curr. Opin. Chem. Biol., 2001, 5(4), 396-401.
76. Chang, T-K.; Chen, J.; Benetton, S. A. In vitro effect of standardized ginseng extracts and individual ginsenosides on the catalytic activity of human CYP1A1, CYP1A2, and CYP1B1. Drug Metab. Dispos., 2002, 30(4), 378-384.
77. He, N.; Edeki, T. The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Am. J. Ther., 2004, 11(3), 206-212.
78. Liu, Y.; Li, W.; Li, P.; Deng, M-C.; Yang, S-L.; Yang, L. The inhibitory effect of intestinal bacterial metabolite of ginsenosides on CYP3A activity. Biol. Pharm. Bull., 2004, 27(10), 1555-1560.
79. Liu, Y.; Ma, H.; Zhang, J-W.; Deng, M-C.; Yang, L. Influence of ginsenoside Rh1 and F1 on human cytochrome p450 enzymes. Planta Med., 2006, 72(2), 126-131.
80. Liu, Y.; Zhang, J-W.; Li, W.; Ma, H.; Sun, J.; Deng, M-C.; Yang, L. Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes. Toxicol. Sci., 2006, 91(2), 356-364.
81. Hao, M.; Zhao, Y-Q.; Chen, P-Z.; Huang, H.; Liu, H.; Jiang, H-L.; Zhang, R-W.; Wang, H. Structure-activity relationship and substrate- dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes. PLoS One, 2008, 3(7), e2697.
82. Shitara, Y.; Sato, H.; Sugiyama, Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 689-723.
83. Kim, S-W.; Kwon, H-Y.; Chi, D-W.; Shim, J-H.; Park, J-D.; Lee, Y-H.; Pyo, S.; Rhee, D-K. Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg3. Biochem. Pharmacol., 2003, 65(1), 75-82.
84. Zhang, J-W.; Zhou, F.; Wu, X-L,; Gu, Y.; Ai, H.; Zheng, Y-T.; Li, Y-N.; Zhang, X-X.; Hao, G.; Sun, J-G.; Peng, Y.; Wang, G-J. 20(S)-Ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions. Drug Metab. Dispos., 2010, 38(12), 2179-2187.
85. Jin, J.; Shahi, S.; Kang, H-K.; van Veen, H.W.; Fan, T-P. Metabolites of ginsenosides as novel BCRP inhibitors. Biochem. Biophys. Res. Commun., 2006, 345(4), 1308-1314.
86. Zhang, J-W.; Zhou, F.; Wu, X-L.; Zhang, X-X.; Chen, Y-C.; Zha, B.S.; Niu, F.; Lu, M.; Hao, G.; Sun, Y.; Sun, J-G.; Peng, Y.; Wang, G-J. Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. Br. J. Pharmacol., 2012, 165(1) 120-134.
87. Chang, T-C.; Huang, S-F.; Yang, T-C.; Chan, F-N.; Lin, H-C.; Chang, W-L. Effect of ginsenosides on glucose uptake in human Caco-2 cells is mediated through altered Na+/glucose cotransporter 1 expression. J. Agric. Food Chem., 2007, 55(5), 1993-1998.
88. Tang, W.; Eisenbrand, G. Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Springer-Verlag: Berlin Heidelberg, 1992, pp. 568-588.
89. Zhang, Q-Y.; Ye, M. Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice). J. Chromatogr. A, 2009, 1216(11), 1954-1969.
90. Kitagawa, I. Licorice root. A natural sweetener and an important ingredient in Chinese medicine. Pure Appl. Chem., 2002, 74(7), 1189-1198.
91. Kuramoto, T.; Yamamoto, S. Monoglucuronylglycyrrhetic acid (MGGR) from glycyrrhizic by acid by ?-glucuronidase and it use as a sweetener in foods. Shokuhin Kogyoh, 1990, 33(1), 46-50.
92. Sung, M.W.; Li, P.C.H. Chemical analysis of raw, dry-roasted, and honey-roasted licorice by capillary electrophoresis. Electrophoresis, 2004, 25(20), 3434-3440.
93. Segal, R.; Mansour, M.; Zaitschek, D.V. Effect of ester groups on the haemolytic action of some saponins and sapogenins. Biochem. Pharmacol., 1966, 15(10), 1411-1416.
94. Isbrucker, R.A.; Burdock, G.A. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul. Toxicol. Pharmacol., 2006, 46(3), 167-192.
95. Asl, M.N.; Hosseinzadeh, H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother. Res., 2008, 22(6), 709-724.
96. van Rossum, T.G.J.; Vulto, A.G.; de Man, R.A.; Brouwer, J.T.; Schalm, S.W. Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol. Ther., 1998, 12(3), 199-205.
97. Yamamoto, S.; Maekawa, Y.; Imamura, M.; Hisajima, T. Treatment of hepatitis with the antiallergic drug, Stronger Neo- Minophagen C. Clin. Med. Pediatr., 1958, 13, 73-75.
98. Suzuki, H.; Ohta, Y.; Takino, T.; Fujisawa, K.; Hirayama, C. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis - double blind trial. Asian Med. J., 1983, 26(7), 423-438.
99. Miyake, K.; Tango, T.; Ota, Y.; Mitamura, K.; Yoshiba, M.; Kako, M.; Hayashi, S.; Ikeda, Y.; Hayashida, N.; Iwabuchi, S.; Sato, Y.; Tomi, T.; Funaki, N.; Hashimoto, N.; Umeda, T.; Miyazaki, J.; Tanaka, K.; Endo, Y.; Suzuki, H. Efficacy of stronger neominophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis. J. Gastroenterol. Hepatol., 2002, 17(11), 1198-1204.
100. Kumada, H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology, 2002, 62(Suppl 1), 94-100.
101. Revers, F.E. Heeft Succus Liquiritae een Genezende Werking op de Maagzweer? Nederlands Tijdschr. Geneeskunde, 1946, 90(7-80), 135-137.
102. van Gelderen, C.E.; Bijlsma, J.A.; van Dokkum, W.; Savelkoul, T.J. Glycyrrhizic acid: the assessment of a no effect level. Hum. Exp. Toxicol., 2000, 19(8), 434-439.
103. Krähenbühl, S.; Hasler, F.; Krapf, R. Analysis and pharmacokinetics of glycyrrizic acid and glycyrrhetinic acid in humans and experimental animals. Steroids, 1994, 59(2), 121-126.
104. Ploeger, B.; Mensinga, T.; Sips, A.; Seinen, W.; Meulenbelt, J.; DeJongh, J. The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling. Drug Metab. Rev., 2001, 33(2), 125-147.
105. Wang, Z.; Kurosaki, Y.; Nakayama, T.; Kimura, T. Mechanism of gastrointestinal absorption of glycyrrhizin in rats. Biol. Pharm. Bull., 1994, 17(10), 1399-1403.
106. Takeda, S.; Ishthara, K.; Wakui, Y.; Amagaya, S.; Maruno, M.; Akao, T.; Kobashi, K. Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J. Pharm. Pharmacol., 1996, 48(9), 902-905.
107. Ishida, S.; Sakiya, Y.; Ichikawa, T.; Taira, Z. Dose-dependent pharmacokinetics of glycyrrhizin in rats. Chem. Pharm. Bull., 1992, 40(7), 1917-1920.
108. Tsai, T-H.; Liao, J-F.; Shum, A. Y-C.; Chen, C-F. Pharmacokinetics of glycyrrhizin after intravenous administration to Rats. J. Pharm. Sci., 1992, 81(9), 961-963.
109. Ishida, S.; Sakiya, Y.; Ichikawa, T.; Awazu, S. Pharmacokinetics of glycyrrhetic acid, a major metabolite of glycyrrhizin, in rats. Chem. Pharm. Bull., 1989, 37(9), 2509-2513.
110. Yamamura, Y.; Kawakami, J.; Santa, T.; Kotaki, H.; Uchino, K.; Sawada, Y.; Tanaka, N.; Iga, T. Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method. J. Pharm. Sci., 1992, 81(10), 1042-1046.
111. Tanaka, N.; Yamamura, Y.; Santa, T.; Kotaki, H.; Uchino, K.; Sawada, Y.; Aikawa, T.; Osuga, T.; Iga, T. Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis. Biopharm. Drug Dispos., 1993, 14(7), 609-614.
112. Krähenbühl, S.; Hasler, F.; Frey, B. M.; Frey, F. J.; Brenneisen, R.; Krapf, R. Kinetics and dynamics of orally administered 18 betaglycyrrhetinic acid in humans. J. Clin. Endocrinol. Metab., 1994, 78(3), 581-585.
113. Cantelli-Forti, G.; Maffei, F.; Hrelia, P.; Bugamelli, F.; Bernardi, M.; D'Intino, P.; Maranesi, M.; Raggi, M.A. Interaction of licorice on glycyrrhizin pharmacokinetics. Environ. Health Perspect., 1994, 102(Suppl 9), 65-68.
114. Wang, Z.; Nishioka, M.; Kurosaki, Y.; Nakayama, T.; Kimura, T. Gastrointestinal absorption characteristics of glycyrrhizin from glycyrrhiza extract. Biol. Pharm. Bull., 1995, 18(9), 1238-1241.
115. Cantelli-Forti, G.; Raggi, M.A.; Bugamelli, F.; Maffei, F.; Villari, A.; Trieff, N.M. Toxicological assessment of liquorice: biliary excretion in rats. Pharmacol. Res., 1997, 35(5), 463-470.
116. Hou, Y-C.; Hsiu, S-L.; Ching, H.; Lin, Y-T.; Tsai, S-Y.; Wen, KC.; Chao, P-D. L. Profound difference of metabolic pharmacokinetics between pure glycyrrhizin and glycyrrhizin in licorice decoction. Life Sci., 2005, 76(10), 1167-1176.
117. Gao, Q-T.; Chen, X-H.; Bi, K-S. Comparative pharmacokinetic behavior of glycyrrhetic acid after oral administration of glycyrrhizic acid and Gancao-Fuzi-Tang. Biol. Pharm. Bull., 2004, 27(2), 226-228.
118. Ishida, S.; Ichikawa, T.; Sakiya, Y. Binding of glycyrrhetinic acid to rat plasma, rat serum albumin, human serum, and human serum albumin. Chem. Pharm. Bull., 1988, 36(1), 440-443.
119. Ishida, S.; Sakiya, Y.; Ichikawa, T.; Kinoshita, M.; Awazu, S. Binding of glycyrrhizin to human serum and human serum albumin. Chem. Pharm. Bull., 1989, 37(1), 226-228.
120. Ishida, S.; Kinoshita, M.; Sakiya, Y.; Taira, Z.; Ichikawa, T. Glycyrrhizin binding site on human serum albumin. Chem. Pharm. Bull., 1992, 40(1), 275-278.
121. Koga, K.; Tomoyama, M.; Ohyanagi, K.; Takada, K. Pharmacokinetics of glycyrrhizin in normal and albumin-deficient rats. Biopharm. Drug Dispos., 2008, 29(7), 373-381.
122. Dai, J-Y.; Yang, J-L.; Li, C. Transport and metabolism of flavonoids from Chinese herbal remedy Xiaochaihu-tang across human intestinal Caco-2 cell monolayers. Acta Pharmacol. Sin., 2008, 29(9), 1086-1093.
123. Parke, D.V.; Pollock, S.; Williams, R.T. The fate of tritiumlabelled β-glycyrrhetic acid in the rat. J. Pharm. Pharmacol., 1963, 15(1), 500-506.
124. Shibata, N.; Shimokawa, T.; Jiang, Z.; Jeong, Y.; Ohno, T.; Kimura, G.; Yoshikawa, Y.; Koga, K.; Murakami, M.; Takada, K. Characteristics of intestinal absorption and disposition of glycyrrhizin in mice. Biopharm. Drug Dispos., 2000, 21(3), 95-101.
125. Sasaki, K.; Yonebayashi, S.; Yoshida, M.; Shimizu, K.; Aotsuka, T.; Takayama, K. Improvement in the bioavailability of poorly absorbed glycyrrhizin via various non-vascular administration routes in rats. Int. J. Pharm., 2003, 265(1-2), 95-102.
126. Fujioka, T.; Kondou, T.; Fukuhara, A.; Tounou, S.; Mine, M.; Mataki, N.; Hanada, K.; Ozaka, M.; Mitani, K.; Nakaya, T.; Iwai, T.; Miyakawa, H. Efficacy of a glycyrrhizin suppository for the treatment of chronic hepatitis C: a pilot study. Hepatol. Res., 2003, 26(1), 10-14.
127. Hattori, M.; Sakamoto, T.; Kobashi, K.; Namba, T. Metabolism of glycyrrhizin by human intestinal flora. Planta Med., 1983, 48(5), 38-42.
128. Akao, T.; Akao, T.; Kobashi, K. Glycyrrhizin β-D-glucuronidase of Eubacterium sp. from human intestinal flora. Chem. Pharm. Bull., 1987, 35(2), 705-710.
129. Kim, D-H.; Jang, I-S.; Lee, S-W. Bacteroides J-37, a human intestinal bacterium, produces α-glucuronidase. Biol. Pharm. Bull., 1997, 20(8), 834-837.
130. Kim, D-H.; Hong, S-W.; Kim, B-T.; Bae, E-A.; Park, H-Y.; Han, M-J. Biotransformation of glycyrrhizin by human intestinal bacteria and its relation to biological activities. Arch. Pharm. Res., 2000, 23(2), 172-177.
131. Akao, T. Hydrolysis of glycyrrhetyl mono-glucuronide to glycyrrhetic acid by glycyrrhetyl mono-glucuronide β-D-glucuronidase of Eubacterium sp. GLH. Biol. Pharm. Bull., 1997, 20(12), 1245-1249.
132. Akao, T. Purification and characterization of glycyrrhetic acid mono-glucuronide beta-D-glucuronidase in Eubacterium sp. GLH. Biol. Pharm. Bull., 1999, 22(1), 80-82.
133. Hattori, M.; Sakamoto, T.; Yamagishi, T.; Sakamoto, K.; Konishi, K.; Kobashi, K.; Namba, T. Metabolism of glycyrrhizin by human intestinal flora. 2. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and relatedcompounds. Chem. Pharm. Bull., 1985, 33(1), 210-217.
134. He, J-X.; Akao, T.; Tani, T. Repetitive administration of Shaoyao- Gancao-tang to rats restores the bioavailability of glycyrrhizin reduced by antibiotic treatment. J. Pharm. Pharmacol., 2003, 55(11), 1569-1575.
135. Dobrinska, M.R. Enterohepatic circulation of drugs. J. Clin. Pharmacol., 1989, 29(7), 577-580.
136. Roberts, M.S.; Magnusson, B.M.; Burczynski, F.J.; Weiss, M. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin. Pharmacokinet., 2002, 41(10), 751-790.
137. Ichikawa, T.; Ishida, S.; Sakiya, Y.; Sawada, Y.; Hanano, M. Biliary excretion and enterohepatic cycling of glycyrrhizin in rats. J. Pharm. Sci., 1986, 75(7), 672-675.
138. Hasler, F.; Krapf, R.; Brenneisen, R.; Bourquin, D.; Krähenbü hl, S. Determination of 18 β-glycyrrhetinic acid in biological fluids from humans and rats by solid-phase extraction and high-performance liquid chromatography. J. Chromatogr., 1993, 620(1), 73-82.
139. Kawakami, J.; Yamamura, Y.; Santa, T.; Kotaki, H.; Uchino, K.; Sawada, Y.; Iga, T. Kinetic-analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats - role of enterohepatic circulation. J. Pharm. Sci., 1993, 82(3), 301-305.
140. Ichikawa, T.; Ishida, S.; Sakiya, Y.; Akada, Y. High-performance liquid chromatographic determination of glycyrrhizin and glycyrrhetinic acid in biological materials. Chem. Pharm. Bull., 1984, 32(9), 3734-3738.
141. Zeng, C-X.; Yang, Q.; Hu, Q. A comparison of the distribution of two glycyrrhizic acid epimers in rat tissues. Eur. J. Drug Metab. Pharmacokinet., 2006, 31(4), 253-258.
142. Yamamura, Y.; Kawakami, J.; Santa, T.; Kotaki, H.; Uchino, K.; Sawada, Y.; Iga, T. Selective high-performance liquid chromatographic method for the determination of glycyrrhizin and glycyrrhetic acid-3-O-glucuronide in biological fluids: application of ionpair extraction and fluorescence labelling agent. J. Chromatogr., 1991, 567(1), 151-160.
143. Akao, T.; Akao, T.; Hattori, M.; Kanaoka, M.; Yamamoto, K.; Namba, T.; Kobashi, K. Hydrolysis of glycyrrhizin to 18β- glycyrrhetyl monoglucuronide by lysosomal beta-D-glucuronidase of animal livers. Biochem. Pharmacol., 1991, 41(6-7), 1025-1029.
144. Sasaki, K.; Yonebayashi, S.; Yoshida, M.; Shimizu, K.; Aotsuka, T.; Takayama, K. Improvement in the bioavailability of poorly absorbed glycyrrhizin via various non-vascular administration routes in rats. Int. J. Pharm., 2003, 265(1-2), 95-102.
145. Ishida, S.; Sakiya, Y.; Ichikawa, T.; Taira, Z. Uptake of glycyrrhizin by isolated rat hepatocytes. Biol. Pharm. Bull., 1993, 16(3), 293-297.
146. Shimamura, H.; Suzuki, H.; Tagaya, O.; Horie, T.; Sugiyama, Y. Biliary excretion of glycyrrhizin in rats: kinetic basis for multiplicity in bile canalicular transport of organic anions. Pharm. Res., 1996, 13(12), 1833-1837.
147. Ho, R.H.; Kim, R.R. Transporters and drug therapy: implications for drug disposition and disease. Clin. Pharmacol. Ther., 2005, 78(3), 260-277.
148. Ismair, M.G.; Stanca, C.; Ha, H.R.; Renner, E.L.; Meier, P.J.; Kullak- Ublick, G.A. Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver. Hepatol. Res., 2003, 26(4), 343-347.
149. Jin, H-Y.; Yamamoto, N.; Uchida, K.; Terai, S.; Sakaida, I. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino aciddefined diet. Biochem. Biophys. Res. Commun., 2007, 364(4), 801-807.
150. Makino, T.; Ohtake, N.; Watanabe, A.; Tsuchiya, N.; Imamura, S.; Iizuka, S.; Inoue, M.; Mizukami, H. Down-regulation of a hepatic transporter multidrug resistance-associated protein 2 is involved in alteration of pharmacokinetics of glycyrrhizin and its metabolites in a rat model of chronic liver injury. Drug Metab. Dispos., 2008, 36(7), 1438-1443.
151. Iveson, P.; Lindup, W.E.; Parke, D.V.; Williams, R.T. The metabolism of carbenoxolone in the rat. Xenobiotica, 1971, 1(1), 79-95.
152. Jing, J.; Ren, W-H.; Chen, X-J.; Wang, Y.; Yu, Q-L.; Wang, G-J.; Davey, A.K.; Wang, J-P.; Jing, N. Glucuronide-sulfate diconjugate as a novel metabolite of glycyrrhetic acid in rat bile. Drug Metab Pharmacokinet., 2008, 23(3), 175-180.
153. Lu, Y.; Zhu, J.; Chen, X-J.; Li, N.; Fu, F-F.; He, J-K.; Wang, G-J.; Zhang, L-L.; Zheng, Y.; Qiu, Z-X.; Yu, X.; Han, D-E.; Wu, L. Identification of human UDP-glucuronosyltransferase isoforms responsible for the glucuronidation of glycyrrhetinic acid. Drug Metab. Pharmacokinet., 2009, 24(6), 523-528.
154. Akao, T.; Akao, T.; Kobashi, K. Metabolism of glycyrrhetic acid by rat liver microsomes: glycyrrhetinate dehydrogenase. Biochim. Biophys. Acta, 1990, 1042(2), 241-246.
155. Akao, T.; Aoyama, M.; Akao, T.; Hattori, M.; Imai, Y.; Namba, T.; Tezuka, Y.; Kikuchi, T.; Kobashi, K. Metabolism of glycyrrhetic acid by rat liver microsomes-II. 22 alpha- and 24-hydroxylation. Biochem. Pharmacol., 1990, 40(2), 291-296.
156. Fugh-Berman, A. Herb-drug interactions. Lancet, 2000, 355(9198), 134-138.
157. Ioannides, C. Pharmacokinetic interactions between herbal remedies and medicinal drugs. Xenobiotica, 2002, 32(6), 451-478.
158. Zhou, S-F.; Gao, Y-H.; Jiang, W-Q.; Huang, M.; Xu, A-L.; Paxton, J.W. Interactions of herbs with cytochrome P450. Drug Metab. Rev., 2003, 35(1), 35-98.
159. Colalto, C. Herbal interactions on absorption of drugs: Mechanisms of action and clinical risk assessment. Pharmacol. Res., 2010, 62(3), 207-227.
160. Paolini, M.; Pozzetti, L.; Sapone, A.; Cantelli-Forti, G. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci., 1998, 62(6), 571-582.
161. Paolini, M.; Barillari, J.; Broccoli, M.; Pozzetti, L.; Perocco, P.; Cantelli-Forti, G. Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes. Cancer Lett., 1999, 145(1-2), 35-42.
162. Hu, W-Y.; Li, Y-W.; Hou, Y-N.; He, K.; Chen, J-F.; But, P.P.; Zhu, X-Y. The induction of liver microsomal cytochrome P450 by Glycyrrhiza uralensis and glycyrrhetinic acid in mice. Biomed. Environ. Sci., 1999, 12(1), 10-14.
163. Mu, Y.; Zhang, J-N.; Zhang, S-M.; Zhou, H-H.; Toma, D.; Ren, SR.; Huang L.; Yaramus M.; Baum, A.; Venkataramanan, R.; Xie, W. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J. Pharmacol. Exp. Ther., 2006, 316(3), 1369-1377.
164. Tu, J-H.; He, Y-J.; Chen, Y.; Fan, L.; Zhang, W.; Tan, Z-R.; Huang, Y-F.; Guo, D.; Hu, D-L.; Wang, D.; Zhou, H-H. Effect of glycyrrhizin on the activity of CYP3A enzyme in humans. Eur. J. Clin. Pharmacol., 2010, 66(8), 805-810.
165. Yoshida, N.; Koizumi, M.; Adachi, I.; Kawakami, J. Inhibition of P-glycoprotein-mediated transport by terpenoids contained in herbal medicines and natural products. Food Chem. Toxicol., 2006, 44(12), 2033-2039.
166. Yoshida, N.; Takada, T.; Yamamura, Y.; Adachi, I.; Suzuki, H.; Kawakami, J. Inhibitory effects of terpenoids on multidrug resistance- associated protein 2- and breast cancer resistance proteinmediated transport. Drug Metab. Dispos., 2008, 36(7), 1206-1211.
167. Lin, S-P.; Tsai, S-Y.; Hou, Y-C.; Chao, P-D. Glycyrrhizin and licorice significantly affect the pharmacokinetics of methotrexate in rats. J. Agric. Food Chem., 2009, 57(5), 1854-1859.
168. Mishima, M.; Okada, S.; Wakita, Y.; Nakano, M. Promotion of nasal absorption of insulin by glycyrrhetinic acid derivatives. I. J. Pharmacobiodyn., 1989, 12(1), 31-36.
169. Lee, K-J.; Park, H-J.; Shin, Y-H.; Lee, C-H. Effect of glycyrrhizic acid on protein binding of diltiazem, verapamil, and nifedipine. Arch. Pharm. Res., 2004, 27(9), 978-983.
170. Sautour, M.; Mitaine-Offer, A. C.; Lacaille-Dubois, M. A. The Dioscorea genus: a review of bioactive steroid saponins. J. Nat. Med., 2007, 61(2), 91-101.
171. Liu, C-Z.; Zhou, H-Y.; Yan Q. Fingerprint analysis of Dioscorea nipponica by high-performance liquid chromatography with evaporative light scattering detection. Anal. Chim. Acta, 2007, 582(1), 61-68.
172. Xu, X-L.; Zhang, Z-R.; Ke, Z-H. Determination of diosgenin in Dioscorea nipponica by RP-HPLC. Zhongguo Zhong Yao Za Zhi, 2003, 28(9), 885-887.
173. Podolak, I.; Galanty, A.; Sobolewska, D. Saponins as cytotoxic agents: a review. Phytochem. Rev., 2010, 9(3), 425-474.
174. Zhang, J-J.; Meng, Z-Y.; Zhang, M-Y.; Ma, D-S.; Xu, S-X.; Kodama, H. Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clin. Chim. Acta, 1999, 289(1-2), 79-88.
175. Sauvaire, Y.; Ribes, G.; Baccou, J.C. Loubatieères-Mariani, M.M. Implication of steroid saponins and sapogenins in the hypocholesterolemic effect of fenugreek. Lipids, 1991, 26(3), 191-197.
176. Kato, A.; Miura, T.; Fukunaga, T. Effects of steroidal glycosides on blood glucose in normal and diabetic mice. Biol. Pharm. Bull., 1995, 18(1), 167-168.
177. Yin, J.; Kouda, K.; Tezuka, Y.; Tran, Q.L.; Miyahara, T.; Chen, YJ.; Kadota, S. Steroidal glycosides from the rhizomes of Dioscorea spongiosa. J. Nat. Prod., 2003, 66(5), 646-650.
178. Tewtrakul, S.; Itharat, A.; Rattanasuwan, P. Anti-HIV-1 proteaseand HIV-1 integrase activities of Thai medicinal plants known as Hua-Khao-Yen. J. Ethnopharmacol., 2006, 105(1-2), 312-315.
179. Tewtrakul, S.; Itharat, A. Anti-allergic substances from the rhizomes of Dioscorea membranacea. Bioorg. Med. Chem., 2006, 14(24), 8707-8711.
180. Dong, M.; Feng, X-Z.; Wang, B-X.; Wu, L-J.; Ikejima, T. Two novel furostanol saponins from the rhizomes of Dioscorea panthaica Prain et Burkill and their cytotoxic activity. Tetrahedron, 2001, 57(3), 501-506.
181. Dong, M.; Feng, X-Z.; Wang, B-X.; Ikejima, T.; Wu, L-J. Steroidal saponins from Dioscorea panthaica and their cytotoxic activity. Pharmazie, 2004, 59(4), 294-296.
182. Dong, M.; Feng, X-Z.; Wu, L-J.; Wang, B-X.; Ikejima, T. Two new steroidal saponins from the rhizomes of Dioscorea panthaica and their cytotoxic activity. Planta Med., 2001, 67(9), 853-857.
183. Sautour, M.; Mitaine-Offer, A-C.; Miyamoto, T.; Dongmo, A.; Lacaille-Dubois, M-A. A new steroidal saponin from Dioscorea cayenensis. Chem. Pharm. Bull., 2004, 52(11), 1353-1355.
184. Liu, H-W.; Zhao, Q-C.; Cui, C-B.; Kobayashi, H.; Yao, X-S. Bioactive saponins from Dioscorea futschauensis. Pharmazie, 2002, 57(8), 570-572.
185. Sautour, M.; Miyamoto, T.; Lacaille-Dubois, M-A. Steroidal saponins and flavan-3-ol glycosides from Dioscorea villosa. Biochem. Syst. Ecol., 2006, 34(1), 60-63.
186. Yang, C.R.; Zhang, Y.; Jacob, M.R.; Khan, S.I.; Zhang, Y-J.; Li, X-C. Antifungal activity of C-27 steroidal saponins. Antimicrob. Agents Chemother., 2006, 50(5), 1710-1714.
187. Sautour, M.; Mitaine-Offer, A-C.; Miyamoto, T.; Dongmo, A.; Lacaille-Dubois, M-A. Antifungal steroid saponins from Dioscorea cayenensis. Planta Med., 2004, 70(1), 90-92.
188. Shen, P.; Wang, S-L.; Liu, X-K.; Yang, C-R.; Cai, B.; Yao, X-S. A new steroidal saponin from Dioscorea deltoidea Wall var. orbiculata. Chin. Chem. Lett., 2002, 13(9), 851-854.
189. Wojcikowski, K.; Wohlmuth, H.; Johnson, D.W.; Gobe, G. Dioscorea villosa (wild yam) induces chronic kidney injury via profibrotic pathways. Food Chem. Toxicol., 2008, 46(9), 3122-3131.
190. Li, K.; Tang, Y-B.; Fawcett, J.P.; Gu, J-K.; Zhong, D-F. Characterization of the pharmacokinetics of dioscin in rat. Steroids, 2005, 70(8), 525-530.
191. Xu, L-N.; Liu, Y-T.; Wang, T.; Qi, Y.; Han, X.; Xu, Y-W. Development and validation of a sensitive and rapid non-aqueous LCESI- MS/MS method for measurement of diosgenin in the plasma of normal and hyperlipidemic rats: A comparative study. J. Chromatogr. B, 2009, 877(14-15), 1530-1536.
192. Wang, T-J.; Liu, Z-B.; Li, J.; Zhong, M.; Li, J-P.; Chen, X-H.; Bi, K-S. Determination of protodioscin in rat plasma by liquid chromatography- tandem mass spectrometry. J. Chromatogr. B, 2007, 848(2), 363-368.
193. Cao, X.; Yao, Z.; Shao, M.; Chen, H.; Ye, W.; Yao, X. Pharmacokinetics of methyl protodioscin in rats. Pharmazie, 2010, 65(5), 359-362.
194. Yao, Z-H.; Cao, X-Z.; Shao, M.; Pan, Y-M.; Ye, W-C.; Yao, X-S. Determination of plasma protein binding rate of methyl protodioscin with ultrafiltration. Zhongguo Zhong Yao Za Zhi, 2008, 33(11), 1291-1294.
195. Ma, H-Y.; Zhou, Q-L.; Wang, B-X. Studies on the metabolism of DX by intestinal bacteria and the absorbed components in serum. China Pharm., 2002, 13(4), 204-205.
196. Cayen, M.N.; Ferdinandi, E.S.; Greselin, E.; Dvornik, D. Studies on the Disposition of Diosgenin in Rats, Dogs, Monkeys and Man. Atherosclerosis, 1979, 33(1), 71-87.
197. Chu, C.; Qi, L-W.; Liu, E-H.; Li, B.; Gao, W.; Li, P. Radix astragali (astragalus): latest advancements and trends in chemistry, analysis, pharmacology and pharmacokinetics. Curr. Org. Chem., 2010, 14(16), 1792-1807.
198. Ma, X.Q.; Shi, Q.; Duan, J.A.; Dong, T.T.X.; Tsim, K.W.K. Chemical analysis of Radix Astragali (Huangqi) in China: a comparison with its adulterants and seasonal variations. J. Agric. Food Chem., 2002, 50(17), 4861-4866.
199. Qi, L-W.; Yu, Q-T.; Li, P.; Li, S-L.; Wang, Y-X.; Sheng, L-H.; Yi L. Quality evaluation of Radix Astragali through a simultaneous determination of six major active isoflavonoids and four main saponins by high-performance liquid chromatography coupled with diode array and evaporative light scattering detectors. J. Chromatogr. A, 2006, 1134(1-2), 162-169.
200. Gui, S-Y.; Wei, W.; Wang, H.; Wu, L.; Sun, W-Y.; Chen, W-B.; Wu, C-Y. Effects and mechanisms of crude astragalosides fraction on liver fibrosis in rats. J. Ethnopharmacol., 2006, 103(2), 154-159.
201. Wang, S-G.; Li, J-Y.; Huang, H.; Gao, W.; Zhuang, C-L.; Li, B.; Zhou, P.; Kong, D-Y. Anti-hepatitis B virus activities of astragaloside IV isolated from radix Astragali. Biol. Pharm. Bull., 2009, 32(1), 132-135.
202. Xu, X-L.; Ji, H.; Gu, S-Y.; Shao, Q.; Huang, Q-J.; Cheng, Y-P. Modification of alterations in cardiac function and sarcoplasmic reticulum by astragaloside IV in myocardial injury in vivo. Eur. J. Pharmacol., 2007, 568(1-3), 203-212.
203. Navarrete, A.; Arrieta, J.; Terrones, L.; Abou-Gazar, H.; Calis, I. Gastroprotective effect of Astragaloside IV: role of prostaglandins, sulfhydryls and nitric oxide. J. Pharm. Pharmacol., 2005, 57(8), 1059-1064.
204. Chan, W-S.; Durairajan, S-S.; Lu, J-H.; Wang, Y.; Xie, L-X.; Kum, W-F.; Koo, I.; Yung, K-K.; Li, M. Neuroprotective effects of Astragaloside IV in 6-hydroxydopamine-treated primary nigral cell culture. Neurochem. Int., 2009, 55(6), 414-422.
205. Yu, J-X.; Zhang, Y-D.; Sun, S.; Shen, J-P.; Qiu, J.; Yin, X-X.; Yin, H-G.; Jiang, S-J. Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats. Can. J. Physiol. Pharmacol., 2006, 84(6), 579-587.
206. Zhang, W-J.; Hufnagl, P.; Binder, B.R.; Wojta, J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NFkappaB activation and adhesion molecule expression. Thromb. Haemost., 2003, 90(5), 904-914.
207. Nalbantsoy, A.; Nesil, T.; Erden, S.; Caliş, I.; Bedir, E. Adjuvant effects of astragalus saponins macrophyllosaponin B and astragaloside VII. J. Ethnopharmacol., 2011, 134(3), 897-903.
208. Zhang, W-D.; Zhang, C.; Liu, R-H.; Li, H-L.; Zhang, J-T.; Mao, C.; Moran, S.; Chen, C-L. Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sci., 2006, 79(8), 808-815.
209. Du, Y.; Zhang, Q.; Chen, G-G.; Wei, P.; Tu, C-Y. Pharmacokinetics of Astragaloside IV in rats by liquid chromatography coupled with tandem mass spectrometry. Eur. J. Drug Metab. Pharmacokinet., 2005, 30(4), 269-273.
210. Zhang, Q.; Zhu, L-L.; Chen, G-G.; Du, Y. Pharmacokinetics of astragaloside iv in beagle dogs. Eur. J. Drug Metab. Pharmacokinet., 2007, 32(2), 75-79.
211. Gu, Y.; Wang, G.; Pan, G.; Fawcett, J. P.; Sun, J. Transport and bioavailability studies of astragaloside IV, an active ingredient in Radix Astragali. Basic Clin. Pharmacol. Toxicol., 2004, 95(6), 295-298.
212. Wen, X-D.; Qi, L-W.; Li, P.; Bao, K-D.; Yan, X-W.; Yi, L.; Li, CY. Simultaneous determination of calycosin-7-O-beta-D-glucoside, ononin, astragaloside IV, astragaloside I and ferulic acid in rat plasma after oral administration of Danggui Buxue Tang extract for their pharmacokinetic studies by liquid chromatography-mass spectrometry. J. Chromatogr. B, 2008, 865(1-2), 99-105.
213. Huang, C-R.; Wang, G-J.; Wu, X-L.; Li, H.; Xie, H-T.; Lü, H.; Sun, J-G. Absorption enhancement study of astragaloside IV based on its transport mechanism in caco-2 cells. Eur. J. Drug Metab. Pharmacokinet., 2006, 31(1), 5-10.
214. Zhu, J.; Lee, S.; Ho, M.K.; Hu, Y-Q.; Pang, H-H.; Ip, F.C.F; Chin, A.C.; Harley, C.B.; Ip, N.Y.; Wong, Y.H. In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator. Drug Metab. Pharmacokinet., 2010, 25(5), 477-86.
215. Huang, H-Q.; Zhang, X.; Lin, M.; Shen, Y-H.; Yan, S-K.; Zhang, W-D. Characterization and identification of saikosaponins in crude extracts from three Bupleurum species using LC-ESI-MS. J. Sep. Sci., 2008, 31(18), 3190-3201.
216. Bao, Y-W.; Li, C.; Shen, H-W.; Nan, F-J. Determination of saikosaponin derivatives in Radix bupleuri and in pharmaceuticals of the chinese multiherb remedy xiaochaihu-tang using liquid chromatographic tandem mass spectrometry. Anal. Chem., 2004, 76(14), 4208-4216.
217. Chiang, L-C.; Ng, L-T.; Liu, L-T.; Shieh, D-E.; Lin, C-C. Cytotoxicity and anti-hepatitis B virus activities of saikosaponins from Bupleurum species. Planta Med., 2003, 69(8), 705-709.
218. Cheng, P-W.; Ng, L-T.; Chiang, L-C.; Lin, C-C. Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin. Exp. Pharmacol. Physiol., 2006, 33(7), 612-616.
219. Bermejo Benito, P.; Abad Martínez, M.J.; Silván Sen, A.M.; Sanz Gómez, A.; Fernández Matellano, L.; Sánchez Contreras, S.; Díaz Lanza, A.M. In vivo and in vitro antiinflammatory activity of saikosaponins. Life Sci., 1998, 63(13), 1147-1156.
220. Yen, M-H.; Lin, C-C.; Yen, C-M. The immunomodulatory effect of saikosaponin derivatives and the root extract of Bupleurum kaoi in mice. Phytother. Res., 1995, 9(5), 351-358.
221. Hsu, Y-L.; Kuo, P-L.; Lin, C-C. The proliferative inhibition and apoptotic mechanism of Saikosaponin D in human non-small cell lung cancer A549 cells. Life Sci., 2004, 75(10), 1231-1242.
222. Ahn, B-Z.; Yoon, Y-D.; Lee, Y-H.; Kim B-H.; Sok, D-E. Inhibitory effect of bupleuri radix saponins on adhesion of some solid tumor cells and relation to hemolytic action: screening of 232 herbal drugs for anti-cell adhesion. Planta Med., 1998, 64(3), 220-224.
223. Liu, S-J.; Ju, W-Z.; Liu, Z-X.; Chen, W-K.; Xiong, N-N; Tan, H-S. Pharmacokinetic study of saikosaponin a in rat plasma by LC-ESIMS. Chin. Pharmacol. Bull., 2009, 25(10), 1383-1385.
224. Fujiwara, K.; Ogihara, Y. Pharmacological effects of oral saikosaponin a may differ depending on conditions of the gastrointestinal tract. Life Sci., 1986, 39(4), 297-301.
225. Kida, H.; Akao, T.; Meselhy, M.R; Hattori, M. Metabolism and pharmacokinetics of orally administered saikosaponin b1 in conventional, germ-free and Eubacterium sp. A-44-infected gnotobiote rats. Biol. Pharm. Bull., 1998, 21(6), 588-593.
226. Shimizu, K.; Amagaya, S.; Ogihara, Y. Structural transformation of saikosaponins by gastric juice and intestinal flora. J. Pharmacobiodyn., 1985, 8(9), 718-725.
227. Kida, H.; Nakamura, N.; Meselhy, M.R.; Akao, T.; Hattori, M. Isolation and identification of human intestinal bacteria capable of hydrolyzing saikosaponins. J. Trad. Med., 1997, 14(1), 34-40.
228. Kida, H.; Akao, T.; Meselhy, M.R.; Hattori, M. Enzymes responsible for the metabolism of saikosaponins from Eubacterium sp. A- 44, a human intestinal anaerobe. Biol. Pharm. Bull., 1997, 20(12), 1274-1278.
229. Lu, T.; Yang, J-L.; Gao, X-M.; Chen, P.; Du, F-F.; Sun, Y.; Wang, F-Q.; Xu, F.; Shang, H-C.; Huang, Y-H.; Wang, Y.; Wan, R-Z.; Liu, C-X.; Zhang, B-L.; Li, C. Plasma and urinary tanshinol from Salvia miltiorrhiza (Danshen), can be used as pharmacokinetic markers for cardiotonic pills, a cardiovascular herbal medicine. Drug Metab. Dispos., 2008, 36(8):1578-1586.
230. Li, L.; Zhao, Y-S.; Du, F-F.; Yang, J-L.; Xu F., Niu, W.; Ren, YH.; Li, C. Intestinal absorption and presystemic elimination of various chemical constituents present in GBE50 extract, a standardized extract of Ginkgo biloba leaves. Curr. Drug Metab., 2012, 13(5), 494-509.
231. Boxenbaum, H.G.; Bekersky, I.; Jack, M.J.; Kaplan, S.A. Influence of gut microflora on bioavailability. Drug Metab. Rev., 1979, 9(2), 259-279.
232. Nicholson, J.K.; Holmes, E.; Wilson, I.D. Gut microorganisms, mammalian metabolism and personalized health care. Nat. Rev. Microbiol., 2005, 3(5), 431-438.
233. Kararli, T.T. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos., 1995, 16(5): 351-380.
234. Li, P.; Wang, G-J. Robertson, T.A.; Roberts, M.S. Liver transporters in hepatic drug disposition: an update. Curr. Drug Metab., 2009, 10(5), 482-498.
235. Giacomini, K.M.; Huang, S-M.; Tweedie, D.J.; Benet, L.Z.; Brouwer, K.L.R.; Chu, X-Y.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K.M.; Hoffmaster, K.A.; Ishikawa, T.; Keppler, D.; Kim, R.B.; Lee, C.A.; Niemi, M.; Polli, J.W.; Sugiyama, Y.; Swaan, P.W.; Ware J.A.; Wright, S.H.; Yee, S.W.; Zamek-Gliszczynski M.J.; Zhang L. Membrane transporters in drug development. Nat. Rev. Drug Discov., 2010, 9(3), 215-235.
236. Zhou, S-F.; Lim, Y.L.; Chowbay, B. Herbal modulation of Pglycoprotein. Drug Metab. Rev., 2004, 36(1), 57-104.
237. De Smet, P.A.G.M. Clinical risk management of herb-drug interactions. Br. J. Clin. Pharmacol., 2006, 63(3), 258-267.
238. Liu, C-X.; Yi, X-L.; Si, D-Y.; Xiao, X-F.; He X.; Li, Y-Z. Herbdrug interactions involving drug metabolizing enzymes and transporters. Curr. Drug Metab., 2011, 12(9) 835-849.
239. Gurley, B.J.; Gardner, S.F.; Hubbard, M.A.; Williams D.K.; Gentry, W.B.; Cui Y-Y.; Ang, C.Y.W. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin. Pharmacol. Ther., 2002, 72(3), 276-287.